A number of diseases, including, for example Alzheimer's disease (AD) are associated with amyloidosis, a pathogenic process of protein or peptide misfolding and aggregation. The amyloid deposits present in these diseases consist of particular peptides or proteins that are characteristic for each of these diseases but regardless of the particular amino acid sequence of the peptides or proteins involved in each pathology, the amyloid fibrils have a characteristic β-sheet structure and generally share a common aggregation pathway.
In each disease, characterized by amyloidosis, a specific protein or peptide misfolds and/or oligomerizes to form soluble aggregation intermediates, and adopts β-sheet structure en route to fibril formation ultimately forming insoluble amyloid fibers, plaques or inclusions. These insoluble forms of the aggregated protein or peptide form by the intermolecular association of β-strands into β-sheets. Recent evidence suggests that the soluble amyloid oligomers may be the principal cause of toxicity.
To date, amyloid-related disorders cannot be cured or prevented. Alzheimer's disease (AD) often is considered as an archetype amyloid-related disease (Monien et al. (2006) Expert Rev. Neurother. 6: 1293-1306). Currently approved drugs for AD treat the symptoms, rather than the causes of the disease and provide only moderate and temporary relief (Shanmugam et al. (2008) Development in Diagnostic and Therapeutic Strategies for Alzheimer's Disease. Pp. 193-250 In: Research Progress in Alzheimer's Disease and Dementia, Vol. 3 (Ed. Sun, M.-K.), Nova Science Publishers, Inc.). AD is the leading cause of dementia and one of the leading causes of death among elderly people (Alzheimer's Disease Supersedes Diabetes As Sixth Leading Cause Of Death In The United States. (Medical News Today, 2008)). In the general population, AD is the 6th cause of death (Id.). A recent report by the Alzheimer Association has suggested that in 2007, the prevalence of AD in the US exceeded 5 million and may increase to 16 million by the middle of the century if no cure is found (see, e.g., (2007) Every 72 seconds someone in America develops Alzheimer's. http://www.alz.org/news_and_events_rates_rise.asp). As the population ages, this situation may lead to an epidemic. Current estimates of cost of care for patients with AD in the US are over $148 billion a year (Id.). Globally, the prevalence of AD is estimated at ˜27 million patients (Maslow et al. (2008) Alzheimer's & Dementia 4(2): 110-133).
Following the modified Amyloid Cascade Hypothesis (Hardy and Selkoe (2002) Science 297: 353-356), leading strategies have focused on Aβ as a primary cause of AD and therefore target inhibition of Aβ production, enhancement of Aβ clearance, or disruption of Aβ assembly. The normal physiologic function of Aβ is unknown, thus inhibiting its production or increasing its clearance may lead to adverse side effects. In fact, very recent data show that depletion of Aβ from rodent brain results in cognitive deficits, that can be rescued with sub-nM concentrations of human Aβ, demonstrating that at low concentration, Aβ is essential for normal brain function (Arancio, O., Amyloid-β: From physiology to pathology (S2-02-04); Mathews, P. M., Endogenous Aβ enhances memory retention in the rat (O2-02-01), International Conference on Alzheimer's Disease, Chicago, 2008). At higher concentrations, such as those that occur in the brains of people with AD, Down's syndrome, or cerebral amyloid angiopathy (CAA), Aβ self-association into oligomers and polymers is purely a pathologic phenomenon and therefore is an attractive target for development of inhibitors (Selkoe (2001) Physiol. Rev. 81: 741-766).
Aβ is produced as a non-toxic, “naturally unstructured” monomeric protein. With aging, Aβ accumulates and self-assembles into highly neurotoxic, soluble oligomers. The oligomers injure susceptible neurons and go on to form polymers that precipitate in the brain as amyloid plaques—one of the pathologic hallmarks of AD.
Because historically, Aβ polymers have been known for a long time and had been thought to be the cause of AD, multiple examples of small molecule inhibitors of Aβ fibrillization exist in the literature (Soto and Estrada (2005) Subcell. Biochem. 38: 351-364). Recently, following a paradigm shift in the amyloid field that identified pre-fibrillar oligomers as the primary cause of cytotoxicity (Kirkitadze et al. (2002) J. Neurosci. Res. 69: 567-577), several groups reported inhibitors of Aβ oligomeriztion (Wang et al. (2004) J. Med. Chem. 47: 3329-3333; Walsh et al. (2005) J. Neurosci. 25: 2455-2462; Yang et al. (2005) J. Biol. Chem. 280: 5892-5901; Necula et al. (2007) J. Biol. Chem. 282, 10311-10324; McLaurin et al. (2006) Nat. Med. 12, 801-808; Ehrnhoefer et al. (2008) Nat Struct Mol Biol 15, 558-566). Inhibitor selection in these studies was based on empirical findings, however, rather than structure-based rational design. Therefore, little can be deduced about their mechanism of action. In contrast, structure-based inhibitor design approaches can provide mechanistic data that can be used to improve inhibitor efficacy and pharmacokinetics.